Process for the production of diamino-alcohols of the aromatic series



Patented July 7, 1933 UNITED" STATES PATENT OFFICE PROCESS FOR THEPRODUCTION OF DI-' AMINO -ALCOHOLS SERIES OF THE AROMATIC GustavHeilner, Berlin-Fichtengrund, Post Friedrichsthal, Germany,

assignor to Chemische Fabriken Dr. Joachim Wiernik & (30.,Aktiengesellschaft, Berlin-Waidmannslust Germany No Drawing. ApplicationJanuary 26, 1934, Serial No. 708,517. In Germany February 1, 1933 1Claim.

The present invention relates to a process for the production ofdiamino-alcohols of the arcmatic series of the type:

in whichRi denotes an aromatic radicle, R2 hydrogen or methyl, R3 adiaminoalkyl radicle and C H C O-CHB1'CH:+2CH:NHCHz-CH:N(CZH5):)

u-bromopropiophenone 1 methylamino 2 diethylamino ethane CHa N1-phenyl-2-(metby1-(diethylaminoethyl-aminopropane-l-one.

l-phenyl-2-(methyl-(diethylaminoethyl))-aminopropane-l-one.

R4 hydrogen or a hydrocarbon radicle. The pro-v duction of saiddiamino-alcohols is efiected by treating aliphatic aromatic compounds,having one or two oxygen atoms in the side chain, with diamines in which1 nitrogen atom is in tertiary, and the other in primary or secondarycombination, the resulting reaction products being -re-" duced ifnecessary.

The operations are performed in the manner customary for the productionof the monoamino alcohols, such as ephedrin. According to the presentinvention however, the monoamines 1-phenyl-2(methyl-(diethylammoethyl))-aminopropane-l-ol 2. If analiphatic-aromatic a-dioxide compound, of the type R.CO.CO.X (in which Rdenotes an aromatic radicle and X hydrogen or methyl) be caused to reactwith diamines containing one nitrogen atom in tertiary, and the other inprimary, combination, water is split off and a condensation product isobtained which furnishes the desired diamino-alcohol on reduction. Inthis reduction, the double linkage of the azornethine is saturated byhydrogen and, at the same time, the keto-group is converted into asecondary-alcohol group. 7

Phenylpropandione brought into reaction in the aforesaid case arereplaced by diamines, so that amino-alcohols with 2 nitrogen atomsresult.

The procedure according to the present invention, consists inintroducing the diamine, either in compounds already possessing alcoholcharacter, or else'in compounds containing keto-groups which areafterwards reduced to alcoholgroups.

lamino-24iethylamino-ethane These two processes can also be performed ina single Working stage, by effecting the condensation in the presence ofreducing agents CoHsC 0-C OCH3+NH2C H2OHzN(C2H5)2 Phenylpropandione.l-amino-2-diethylaminoethane EXAMPLE I' RACEMIC l-PHENYL-Z- (METHYL-(DiETHYLAMINO- ETHYL) )-AMINOPROPANE-1-OL (1) 1 -phenyZ-2- (methyl-(diethylaminoethyl) aminopropanone A solution of 21.3 grams ofu-bromopropiophenone in 50 cc. of ether is treated with 26 grams of amethylamine p diethylaminoethane, accompanied by cooling. Theprecipitation of a-meth'yL amino-fi-diethylaminoethane-hydrobromidecommences after a short time. After leaving the mixture at rest forseveral hours in the cold, the reaction is completed by gentle heating.The precipitated salt is separated by filtration, and the oily'residueis distilled in vacuo. Under a pressure of about 1 mm. the1-pheny1-2-(methyl-(diethyl- Phenylpropanolone.

1-phenyl-2-(diethylaminoethyl)-aminopropane-l-ol In this case also, thetwo working stages maybe combined, if the condensation of theketo-alcohol with the diamine be effected in presence of reducingagents.

Phenylpropanolone I-aminQ-Z'dicthylaminoethane 4. If I a fatty-aromatichalogenalcohol R.CH(OI-I)'.'CH (halogen) X (in which R denotes anaromatic radicle, and X hydrogen or methyl) be caused to react withdiamines containing l'nitrogen atom in tertiary combination, the desireddiamino-alcohol will be formed.

In such case','however, it is preferable to start, not withhalogen-alcohols, but with the corresponding ethers, the ether beingsubsequently split up. V c

aminoethyl))-aminopropanone passes over at 132-13 4 0., as a yellowishoil, which darkens on being lefte'xposed in the air. The yield of pureproduct is zi'gmms (i. e. about of theory).

(2) Racemic 1 phenyZ-Z-(methyl (diethylaminoethyl) -aminopropane-1-ol Asolution of 13.1 grams of the keto-base, (obtained as in 1) in thecalculated quantity of dilute aqueous hydrochloric acid, is treated with25 grams of a palladium and barium sulphate catalyst, containing 0.5grams of metallic palladium, and agitated in presence of hydrogen. Afterthe calculated amount of hydrogen has been absorbed, the catalyst isfiltered ofi" and the reducl-methylamino-2 diethylaminoethane.

CHr-CHr-N(C2H5)2 1-phenyl1-methoxy-2- (methyl- (diethylaminoethyl)-aminopropane.

1-phenyl-2-(methyl-(diethylaminoethyl))-an1inopropane-l-ol- Ihydrobromide The resulting products possess valuable therapeuticproperties, and are intended for the treatment of asthma.

ti'on prpauais set free by addition of alkali.

Under apressure of 1.5-2 mm; the racemic 1- phnyI-Z- (methyl-(diethylaminoethyl) aminopropane-l-ol boils at 140-141" C. An almosttheoretical yield is obtained. The dihydrochlorlde obtained byprecipitating the ethereal solution of the base with etherealhydrochloric acid, is a hygroscopic crystalline mass. Analysis showed20.8 of chlorine (theory 21.04% Cl).

EXAlVl'PLE 2 (1 p-Methoxy-w- (methyl- (diethylaminoethyl) AMINOETHYL))-AMINOETHANE-1-0L (1) p-methoacy-w- (methyl- (diethylaminoethyl)aminoacetophenone 18.5 grams of p-methoxy-w-chloracetophenone (Ber.deutsch.chem.Ges., 30 (1897), p. 1715) are distributed in 50 cc. ofbenzene and gradually treated with 26 grams ofa-methylamino-p-diethylaminoethane. Spontaneous heating, tempered byintermittent cooling, occurs, the halogenketone passing into solution,whilst a-methylamino-p-diethylaminoethane hydrochloride is precipitated.After standing for several hours at room temperature, followed by abrief moderate heating, the reaction mixture is agitated with water,whereupon the precipitated salt redissolves. The benzene solution isfreed from the solvent in vacuo', the residue is taken up with acetoneand treated with ethereal hydrochloric acid until the reaction solutionis acid to Congo solution as indicator. The dihydrochloride of themethoxy-w- (methyl-diethylaminoethyl) aminoacetophenone thereuponseparates as a rapidly solidifying oil. The salt is very sparinglysoluble in acetone. It is crystallized from a mixture of acetone with asmall amount of alcohol, and melts, with decomposition, at 170-471 C.Yield: 25 grams of dihydrochloride (71% of the theoretical).

(2) 1 (methozcyphenyl) -2- (methyl (diethylaminoethyl) -aminoethane-1 -Z20 grams of the dihydrochloride obtained in 1, are dissolved in waterand agitated with hydrogen, under a slight positive pressure, inpresence of palladinized charcoal. After the theoretical amount ofhydrogen has been absorbed, the catalyst is filtered off, the liquidbeing rendered alkaline and extracted with ether, and the extractionresidue distilled in vacuo. The l- (p-methoxyphenyl) -2- (methyl-(diethylaminoethyl))-aminoethane-1-ol passes over at 185- 190 C.(pressure mm.). The dihydrochloride melts at 158160 C.

EXAMPLE 3 I'PHENYL- (DIETHYLAMINOETHYL) 'AMINOPM PANE-l-OL 23.2 grams of1-amino-2-diethylaminoethane (Berichte, 29, p. 2526) in 100 cc. ofmethyl alcohol are mixed with a solution of 6.4 grams of sulphurous acidin 150 cc. of methyl alcohol, 20 grams of zinc dust being added and thewhole actively stirred. The mixture is heated to boiling, under a refluxcondenser. In the course of about 2 hours, 20 grams ofphenylpropandione, dissolved in 100 cc. of methanol, are dropped in, 11grams of sulphurous acid in 170 cc. of water, and a further 20 grams ofzinc dust being added at the same time.

When reduction is complete, the liquid is 11- tered and acidified, themethanol being distilled off and the solution repeatedly extracted withether in order to remove non-basic constituents. After the solution hasbeen rendered alkaline, the new base is taken up with ether andfractionated under a good vacuum. Under a pressure of about 0.5-1 mm.the racemic 1-phenyl-2- (diethylaminoethyl)aminopropane-1-ol passes overat about 140 C. For further purification it is taken up with alcohol andtreated with alcoholic oxalic acid, the very sparingly soluble oxalate(melting point 180-182 C.) being precipitated. In order to prepare thedihydroiodide, the free base is regenerated from the oxalate by means ofalkali, then neutralized with hydriodic acid, brought to dryness andrecrystallized from isopropyl alcohol. It melts at FIG-178 C.

EXAMPLE 4 1-PHENYL-2- (DIETHYLAMINOETEYL) -AMINO- PROPANE-L01.

15 grams of phenylpropanolone in 30 cc. of ether are treated with 12grams of l-amino-2- diethylaminoethane, and the whole is warmed underthe reflux condenser for a short time. A condensation product with thecharacter of an azomethine is formed, which can be subjected toreduction without further purification. After addition of palladiumcatalyst, the ethereal solution is agitated with hydrogen under pressureuntil the calculated amount of hydrogen has been absorbed. The reductionis then stopped, the catalyst filtered off, and the solution renderedalkaline in order to remove non-basic constituents. The furthertreatment is performed in the same manner as set forth in Example 3.

EXAMPLE 5 1-PHENYL- METHYL- (DIETHYLAMINOETHYL) AMINOPROPANE-l-OL 23grams of 1-phenyl-l-methoxy-2-bromopropane (Berichte, 58 (1925) pp.1260-1270) and 26 grams of 1-methylamino-2-diethylaminoethane are leftin contact for a short time, being then gradually heated and maintainedfor several hours at 100 C. The reaction mixture is diluted with ether,separated from the precipitated 1- methylamino-2-diethylamino-ethanehydrobromide, and the ether is distilled off. The residue is taken upwith dilute hydrochloric acid, the aqueous acid solution is extractedwith ether, to remove non-basic constituents, and after being renderedstrongly alkaline with caustic potash, is again repeatedly extractedwith ether. After the ether has been distilled oif, the liquid is heatedat 100 C. for 1 hour with a threefold quantity of hydrobromic acidsaturated at 0 C. When the liquid has cooled down, it is renderedalkaline, and the liberated base is fractionated in vacuo. Theconstituent passing over at 130- 135 C., under a pressure of about 1mm., represents the desired racemic I-phenyl-Z-(methyl-(diethylaminoethyl) -aminopropane-1-ol.

What I claim and desire to secure by Letters Patent of the United Statesis:

The process which consists in causing fattyaromatic halogen ketones ofthe type:

in which R denotes one element of the group consisting of phenyl andmono methoxy phenyl, X one element of the group consisting of hydrogenand methyl, to react with wherein R5 represents one element of the groupconsisting of hydrogen and methyl and subjecting the diamino-ketonesthus obtained to a reduction.

GUSTAV HEILNER.

